I. Introduction

Epilepsy is the tendency to have recurrent seizures unprovoked by systemic or acute neurologic insults. (Slide 2) Antiepileptic drugs (AEDs) are those which decrease the frequency and/or severity of seizures in people with epilepsy. The older term, anticonvulsant drug, is still sometimes used as a synonym for AED, but is less accurate because many seizures do not involve convulsive movements. There is no convincing evidence that AEDs "cure" or alter the natural history of epilepsy. However, many patients whose seizures have been completely controlled for two or more years can be successfully withdrawn from AEDs. The therapeutic goal is maximizing seizure control while minimizing adverse drug effects, thus improving the patient's quality of life. (Slide 3)

Slide 2

Definitions

Slide 3

Antiepileptic Drug

The first effective AED was potassium bromide, discovered serendipitously in the mid-nineteenth century. Phenobarbital came into use in the early twentieth century, followed by phenytoin in the late 1930s, the latter resulting from systematic investigations by Merritt and Putnam using an animal seizure model. (Slide 4) Trimethodione, discovered in 1944, was the first AED specific for the treatment of absence seizures. Many of the early AEDs were modifications of these compounds. The last decade has seen the development of eight new AEDs. Slides 6 and 7 show chemical structures of several AEDs. Most older drugs share a 5- or 6-membered heterocyclic ring which includes one or two nitrogen atoms and a wide variety of side chains, sometimes containing other ring structures. The shared heterocyclic ring structure may underlie the allergic reactions in some patients to more than one drug. Structures of the newer drugs possess fewer similarities to the older agents and to each other reflecting perhaps unique mechanisms of drug action. (Slide 5)

Slide 4

History of Antiepileptic Drug Therapy in the U.S.

Slide 6

Antiepileptic Drug Therapy Structures of Commonly Used AEDs

Slide 7

Antiepileptic Drug Therapy Structures of Commonly Used AEDs

Slide 5

History of Antiepileptic Drug Therapy in the U.S.

Because AEDs constitute the mainstay of epilepsy therapy, effective treatment requires an understanding of AED pharmacology and pharmacokinetics. Principles of general pharmacology will be reviewed briefly in the specific context of AED use. (Slides 6–8)

Slide 8

Antiepileptic Drug Therapy Structures of Commonly Used AEDs

II. Mechanisms of AED Activity

A seizure is the clinical manifestation of a hyperexcitable neuronal network, in which the electrical balance underlying normal neuronal activity is pathologically altered—excitation predominates over inhibition (see Basic Mechanisms syllabus). Effective seizure treatment generally augments inhibitory processes or opposes excitatory processes. Since the normal resting neuronal membrane potential is intracellularly negative, inhibitory processes make the neuron more electrically negative, hyperpolarizing the membrane, while excitatory processes make the intracellular potential less negative or more positive, depolarizing the cell. On an ionic level, inhibition is typically mediated by inward chloride or outward potassium currents, and excitation by inward sodium or calcium currents. Drugs can directly affect specific ion channels or indirectly influence synthesis, metabolism, or function of neurotransmitters or receptors that control channel opening and closing. The most important central nervous system inhibitory neurotransmitter is gamma-amino-butyric acid (GABA). The most important excitatory neurotransmitter is glutamate, acting through several receptor subtypes. (Slide 9)

Slide 9

Cellular Mechanisms of Seizure Generation

Table 1 summarizes proposed mechanisms of action of the major AEDs. Blocking voltage-gated sodium channels during rapid rates of neuronal discharge appears to be the primary mechanism of action of several AEDs, particularly the two first-line drugs for partial epilepsies, phenytoin and carbamazepine; this mechanism also appears to be at least partly responsible for the antiepileptic effects of newer drugs such as lamotrigine and topiramate. This rate-dependent action is crucial, addressing the requirement that AEDs should affect pathologic more than physiologic neuronal excitation, since a drug with similar effects on all excitation would produce deep coma as an inevitable side effect. (Slides 10–14)

Table 1

Commonly Used AEDs and Proposed Mechanisms of Action (Modified from Macdonald RL, Meldrum BS. Principles of antiepileptic drug action. In Antiepileptic Drugs, Fourth Edition. Levy RH, Mattson RG, Meldrum BS, eds. New York: Raven Press, 1995:61–77. (more...)

Slide 10

AEDs: Molecular and Cellular Mechanisms

Slide 11

AEDs: Molecular and Cellular Mechanisms

Slide 12

AEDs: Molecular and Cellular Mechanisms

Slide 13

AEDs: Molecular and Cellular Mechanisms

Slide 14

AEDs: Molecular and Cellular Mechanisms

The GABA system and its associated chloride channel (Slide 15) is a target of many old and new AEDs effective against many seizure types. Barbiturates and benzodiazepines act directly on subunits of the GABA receptor-chloride channel complex. Barbiturates increase the duration of chloride channel openings, while benzodiazepines increase the frequency of these openings. Tiagabine inhibits GABA re-uptake from synapses. Vigabatrin, a drug not available in the U.S., elevates GABA levels by irreversibly inhibiting its main catabolic enzyme, GABA-transaminase. Gabapentin was designed as a lipophilic GABA analogue, but does not function as a receptor agonist; its mechanism of action is unknown.

Slide 15

The GABA System

Calcium current into the neuron is another important excitatory mechanism. There are several different calcium channel types, but nonselective calcium channel blockers have low antiepileptic efficacy. Ethosuximide selectively blocks transient ("T-type") calcium currents in thalamic neurons, which inhibits the thalamocortical circuits responsible for generating the EEG spike-wave complex underlying absence seizures.

Excitatory neurotransmission mediated by calcium and sodium currents through glutamate receptors has been a tempting target for new AEDs, because these currents may contribute not only to seizure generation but also to neuronal damage from status epilepticus and stroke. Direct glutamate receptor antagonists are effective against experimental seizures, but frequently cause psychosis and other neuropsychiatric adverse effects, preventing clinical use. However, several newer, better tolerated drugs, including lamotrigine and topiramate, may act on this system indirectly.

III. AED Pharmacokinetics

Pharmacokinetics is the quantitative description of what happens to a drug when it enters the body, including drug absorption, distribution, metabolism and elimination/excretion).

A. Absorption

This is determined by route of intake. Most AEDs are available for oral administration, although some have formulations that are also available for intravenous, intramuscular or rectal administration. (Slide 16)

Slide 16

Pharmacokinetic Principles

Oral Absorption

Most AEDs undergo complete or nearly complete absorption when given orally. Most often, administration of AEDs with food slows absorption and can help avert peak dose related side effects. Calcium containing antacids may interfere with phenytoin absorption. Gabapentin is absorbed by a saturable amino acid transport system and does not get absorbed after a certain dose.

Intramuscular Administration

Fosphenytoin may be administered intramuscularly if intravenous access cannot be established in cases of frequent repetitive seizures.

Rectal administration

Diazepam (available as a rectal gel) has been shown to terminate repetitive seizures and can be administered by family members at home.

Intravenous administration

This route is used for emergencies. Phenytoin, fosphenytoin, phenobarbital, diazepam, lorazepam and valproic acid are available as IV preparations (see section on status epileptics for side effects related to intravenous use).

C. Metabolism

Most AEDs are metabolized in the liver by hydroxylation or conjugation. These metabolites are then excreted by the kidney. Some metabolites are themselves active (carbamazepine, oxcarbazepine, primidone). Gabapentin undergoes no metabolism and is excreted unchanged by the kidney.

Most AEDs are metabolized by the P450 enzyme system in the liver. Different AEDs either induce or inhibit certain isoenzymes of this system and can result in changes of the pharmacokinetic properties of different medications (Table 2). In general enzyme inducers decrease the serum concentrations of other drugs metabolized by the system and enzyme inhibitors have the opposite affect. Valproic acid is metabolized by a combination of conjugation by uridine glucuronate (UDP)-Glucuronyltranferase (UGT) via conjugation and by mitochondrial beta-oxidation. (Slides 17–22)

Table 2

Effects on Metabolic Enzymes of AED and Selected Other Drugs. Adding an enzyme inducer to a substrate decreases the serum concentration of the substrate, while withdrawing an inducer or adding an enzyme inhibitor has the opposite effect. (+ usually exhibits (more...)

Slide 17

The Cytochrome P-450 Enzyme System

Slide 18

The Cytochrome P-450 Enzyme System

Slide 19

The Cytochrome P-450 Isozyme System

Slide 20

Drug Metabolizing Enzymes: UDP- Glucuronyltransferase (UGT)

Slide 21

Drug Metabolizing Isozymes and AEDs

Slide 22

Enzyme Inducers/Inhibitors: General Considerations

D. Elimination

Drug elimination rate is usually expressed as the biological half-life and is defined as the time required for the serum concentration to decrease by 50% following absorption and distribution. This changes for some drugs based on serum concentration e.g. phenytoin has a longer half-life at high serum levels. The half-life also determines the dosing frequency required for a drug to be maintained at a steady state in the serum. Most drugs are eliminated by the kidneys and dosage adjustments are required in cases of renal impairment. (Slide 23)

Slide 23

Pharmacokinetic Principles

Slide 24

AED Inducers: General Considerations

Slide 25

Inhibition

Slide 26

AED Inhibitors

Slide 27

Hepatic Drug Metabolizing Enzymes and Specific AED Interactions

Slide 28

Isozyme Specific Drug Interactions

IV. Additional Pharmacokinetic and Pharmacodynamic Aspects of AEDs

A. Therapeutic Index

AEDs can have a narrow range within which seizures are controlled without toxicity. This concept is quantified as the "therapeutic index" (TI). TI is the ratio of the drug concentration effective for 50% of subjects (ED50) to the concentration toxic to 50% of subjects (TD50)—TI=ED50/TD50. The "therapeutic range" of AED serum concentrations is an attempt to translate the experimental concept of therapeutic index to the clinic. These ranges are broad generalizations which are of limited use and can be misleading when applied to individual patients. Many patients tolerate and need serum concentrations above the usual therapeutic range, while others achieve complete seizure control, or even experience adverse effects, at concentrations below it. Table 3 shows these ranges for common AEDs, as well as pharmacokinetic parameters relevant to clinical use. (Slides 29–34)

Table 3

Dosing and Pharmacokinetcis of Commonly Used Antiepileptic Drugs.

Slide 29

Therapeutic Index

Slide 30

Steady State and Half Life

Slide 31

AED Serum Concentrations

Slide 32

AED Serum Concentrations

Slide 33

Potential Target Range of AED Serum Concentrations

Slide 34

Potential Target Range of AED Serum Concentrations

B. Pharmacodynamic Interactions

Drug interactions based on pharmacokinetics, or "what the body does to the drug," must be distinguished from those based on pharmacodynamics, or "what the drug does to the body." Pharmacodynamic effects include both wanted and unwanted drug effects on the brain and other organs. Gabapentin, for example, has no important pharmacokinetic interactions with other AEDs. Because gabapentin and many other drugs can cause sedation and dizziness, however, pharmacodynamic interactions can occur. Ideally, drug combinations should produce additive or synergistic (supra-additive) therapeutic effects and sub-additive toxicities. Drug combinations with different mechanisms of action may help achieve this goal. (Slides 35–37)

Slide 35

AEDs and Drug Interactions

Slide 36

Pharmacodynamic Interactions

Slide 37

Pharmacokinetic Interactions: Possible Clinical Scenarios

C. Patient Influences on Drug Effects

Age and systemic conditions can influence pharmacokinetic and pharmacodynamic parameters. Elimination of many drugs is slower in the elderly, mainly because of reduced hepatic and renal blood flow, which lengthens drug half-life above published values based on young adults. In addition, albumin levels fall with age; this increases the free fraction of drugs that are highly protein bound, thus increasing risk of toxicity, especially for highly protein-bound drugs. Further, older people are often more sensitive to drug effects at a given free level. In the elderly, AEDs should usually be started at a lower dose and increased at a slower rate than in younger patients. (Slide 38)

Slide 38

Pharmacokinetic Factors in the Elderly

Drug metabolism and disposition in children can differ significantly from that in adults. Beyond the neonatal period, when protein binding and drug metabolic rates are low, children usually have faster drug elimination rates and reduced serum half-lives relative to adults. Some children require almost twice the adult mg/kg dosage, particularly if combination therapy with enzyme-inducers is employed. Furthermore, because of shorter pediatric half-lives, most AEDs require at least 3 times daily administration in children 1–10 years of age. (Slide 39)

Slide 39

Pharmacokinetic Factors in Pediatrics

Despite frequent drug administration, large swings in peak-to-peak concentrations are possible, especially in young children, because of their fast elimination rates. Solid oral dosage forms overcome this problem by providing a longer absorption phase that reduces peak and increases trough concentrations. Crushed tablets are preferable to liquids in younger children for similar reasons. Rapid gastrointestinal transit times in children may, however, impede absorption.

Pregnancy increases the volume of distribution and the rate of drug metabolism, and decreases protein binding. For most AEDs, the optimal dose increases as pregnancy progresses. Total and free drug concentrations are helpful guides to adjusting doses in pregnancy (See Clinical Epilepsy syllabus). (Slide 40)

Slide 40

Pharmacokinetics in Pregnancy

Fever can increase the metabolic rate, resulting in more rapid drug elimination and lower serum concentrations. Febrile illnesses may also elevate serum proteins that bind AEDs, resulting in decreased free levels. Severe hepatic disease impairs metabolism, increasing serum levels and risk of toxicity of many drugs. However, complex interactions among hepatic blood flow, biliary excretion, and hepatocellular function make the net effect of hepatic disease on drug levels difficult to predict. Renal disease reduces elimination of some drugs such as gabapentin. In chronic renal disease where there is protein loss, one commonly can see a higher free fraction of highly protein bound AEDs which then are more susceptible to elimination lower serum concentration of the drug. More frequent doses may need to be given. Effects of dialysis differ among AEDs. Some, such as phenobarbital, are significantly removed. Serum concentrations can be measured before and after dialysis, and appropriate boluses given.

V. Adverse Effects

As mentioned previously, most AEDs have a narrow therapeutic window—a small range of serum concentrations within which seizure prevention is achievable without significant toxicity or side effects. This concept applies primarily to dose-related, reversible, short-term side effects. However, risk of idiosyncratic effects such as allergic reactions and organ damage must also be considered. Serious idiosyncratic effects are rare but can be life threatening. They generally occur within several weeks or months of starting the drug, tend to be dose-independent (except possibly for skin rash with lamotrigine), and unpredictable. (Slide 41–43)

Slide 42

Acute, Dose-Related Adverse Effects of AEDs

Slide 41

Adverse Effects

Slide 43

Acute, Dose-Related Adverse Effects of AEDs (cont.)

Intermittent or frequent monitoring of biochemical (e.g., liver functions such as ALT, AST) or hematologic (e.g., CBC) laboratory tests may not detect changes in time to alter prognosis. In addition, frequent monitoring may detect changes or abnormalities which are not clinically significant (e.g., usually transient alterations in liver function tests associated with valproate therapy or commonly-observed, usually transient reductions in leukocyte counts associated with carbamazepine). Education of patients or caregivers to promptly report relevant symptoms of possibly serious idiosyncratic effects accompanied by appropriate laboratory follow-up are currently regarded as mainstays of detection.

Many idiosyncratic reactions likely result from inherited genetic susceptibilities to a particular drug or metabolite. The most common target organs are skin, liver, bone marrow, and occasionally pancreas. Skin rashes are common, immunologically mediated, and usually minor and reversible. Skin rashes, can however, progress to Stevens-Johnson syndrome. The more serious organ toxicities occur in less than 1 in 10,000–100,000 treated patients. Felbamate-related aplastic anemia appears to occur more commonly (approximately 1:5,000). For some AEDs, the presence of predisposing risk factors may increase the risk of serious idiosyncratic reactions. Valproate-related hepatotoxicity is more common in very young children receiving multiple AEDs; lamotrigine-induced skin rashes are more common in patients receiving valproate and/or who are treated with aggressively-titrated lamotrigine doses. (Slides 44–45)

Slide 44

Idiosyncratic Adverse Effects of AEDs

Slide 45

Idiosyncratic Adverse Effects of AEDs

The third type of adverse drug effect is cumulative toxicity, usually occuring over years of treatment. (Slide 46) Because most AEDs other than phenobarbital and phenytoin have been in use for less than 25 years, data regarding these types of adverse effects are limited. Table 4 lists the most common dose-related, idiosyncratic, and cumulative toxicities.

Slide 46

Long-Term Adverse Effects of AEDs

Table 4

Antiepileptic Drug Toxicity . SeeSlides 42–46

References

1. Brodie MJ, Dichter MA. Antiepileptic drugs. N Engl J Med. 1996;334:168–175. [PubMed: 8531974]
2. Engel J Jr. Seizures and epilepsy. Philadelphia: F.A. Davis, 1989.
3. Levy RH, Mattson RH, Meldrum BS, eds. Antiepileptic drugs (4th ed.). New York: Raven Press, 1995.
4. Mattson RH. Selection of drugs for the treatment of epilepsy. Sem Neurol. 1990;10:406–413. [PubMed: 2287835]
5. Perucca E. The clinical pharmacology of the new antiepileptic drugs. Pharmacol Res. 1993;28:89–106. [PubMed: 8278308]
6. Rogawski MA, Porter RJ. Antiepileptic drugs: pharmacological mechanisms and clinical efficacy with consideration of promising developmental stage compounds. Pharmacol Rev. 1990;42:223–286. [PubMed: 2217531]
7. Scheyer RH, Cramer JA. Pharmacokinetics of antiepileptic drugs. Sem Neurol. 1990;10:414–421. [PubMed: 2287836]
8. Smith DB, ed. Epilepsy: Current approaches to diagnosis and treatment. New York: Raven Press, 1990.
9. Wilder BJ, ed. Rational polypharmacy in the treatment of epilepsy. Neurology 45 (Suppl. 2), 1995.
10. Wyllie E, ed. The treatment of epilepsy: Principles and practice. Philadelphia: Lea & Febiger, 1993.

Appendix A: Pediatric Case Study

See Slide 47.

Slide 47

Pharmacology Resident Case Studies

Tommy is a 4 year old child with a history of intractable seizures and developmental delay since birth. He has been tried on several anticonvulsant regimens (i.e., carbamazepine, valproic acid, ethosuximide, phenytoin, and phenobarbital) without significant benefit. (Slide 48) Tommy's seizures are characterized as tonic seizures and atypical absence seizures and has been diagnosed with a type of childhood epilepsy known as Lennox-Gastaut Syndrome. (Slide 49)

Slide 48

Pharmacology Resident Case Studies

Slide 49

Case #1 – Pediatric Con't

1. Briefly describe what characteristics are associated with Lennox-Gastaut Syndrome. (Slide 50)
   Lennox Gastaut Syndrome refers to a devastating epileptic encephalopathy that has its onset in early childhood (usually between the ages of 1 and 7 years) and often persists into adulthood. The epileptic syndrome is characterized by multiple seizure types including tonic, atonic, atypical absence (i.e., staring and decreased response to environmental stimuli), and myoclonic (uncommon) seizures and has been estimated to occur at a prevalence between 1 to 2% for all patients with epilepsy. The EEG pattern has a slow background for age along with a diffuse slow spike-wave patterns of 1.5 – 2.5 Hz.
   The etiology of Lennox-Gastaut Syndrome is variable. It is estimated that 9 to 30% of patients have had a previous history of infantile spasms. Other causes consist of certain prenatal cortical dysplasias and some genetic causes such as tuberous sclerosis. Perinatal and postnatal causes include hypoxia, birth injuries, meningitis, and encephalitis. The incidence of Lennox-Gastaut Syndrome is higher in boys than in girls.
   The seizures are poorly responsive to standard anticonvulsants, and over time most children show evidence of cognitive decline.
2. Which anticonvulsants are currently FDA approved for Lennox-Gastaut Syndrome?
   The four FDA approved anticonvulsants for Lennox Gastaut syndrome are felbamate, lamotrigine, topiramate and valproic acid. In addition, clonazepam, zonisamide, and the ketogenic diet may be helpful.
3. Tommy is currently being treated with ethosuximide 250 mg BID and valproic acid 250 mg BID. The neurologist wants to add another anticonvulsant onto Tommy's current regimen and asks you for your recommendations. (Hint: Evaluate current anticonvulsants based on positive clinical benefit in combination therapy and adverse effect profile.) (Slide 51)
   This question asks you to evaluate potential clinical efficacy literature and adverse effect profiles for lamotrigine, felbamate, and topiramate. Based on adverse effect profiles, both topiramate and lamotrigine have favorable profiles compared with felbamate (i.e., aplastic anemia and hepatic failure). Pisani et al. showed, however, that there was a synergistic effect when valproic acid and lamotrigine were used in combination than either medication used alone. Epilepsia 1999 Aug;40(8):1141–6.
4. Based on your recommendations above, what patient education points would you want to emphasize? (Slide 52)
   The most common adverse effects observed with lamotrigine use include" 5% include dizziness, ataxia, somnolence, headache, diplopia, blurred vision, nausea, vomiting, and rash. Dizziness, diplopia, blurred vision, ataxia, nausea, and vomiting were associated with dose escalations especially in patients concomitantly taking carbamazepine.
   Lamotrigine is associated with high incidence of rash requiring hospitalizations and discontinuation of treatment. The incidence of these rashes, which have been associated with Steven's Johnson Syndrome, is approximately 1% (1/100) in pediatric patients (age < 16 years)and 0.3% (3/1000) in adults. The incidence of rash occurs at a higher rate in patients concomitantly taking valproic acid. If the dose is started low and escalated slowly, the risk of rash is minimized. Parents should be instructed to watch for a red-raised rash especially on the trunk of the body a well as any mucosal involvement around the eyes, nose, or mouth. If rash occurs, instruct parent to contact neurologist and/or primary care physician immediately for evaluation. lamictal (lamotrigine) Review seizure first-aid techniques, seizure precautions as well as medication administration, compliance, and storage issues.

Slide 50

Case #1 – Pediatric Con't

Slide 51

Case #1 – Pediatric Con't

Slide 52

Case #1 – Pediatric Con't